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Methods of detecting and treating microsatellite-instability positive tumors using RIZ

a technology of riz and tumors, applied in the field of cancer, can solve the problems of riz1 expression in tumors in vivo, cell dna mismatch repair system, microsatellite instability, etc., and achieve the effect of inhibiting tumor growth and inhibiting the growth of riz1-positive tumors

Inactive Publication Date: 2005-09-22
THE BURNHAM INST +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a method for inhibiting the growth of a tumor that has a specific genetic mutation called microsatellite instability (MSI). This is done by introducing a specific gene called RIZ1 into the tumor and expressing it there in a way that prevents the tumor from growing. The patent also describes a way to determine if a tumor has MSI by measuring the number of certain nucleotides in a specific gene.

Problems solved by technology

However, the effect of RIZ1 expression in tumors in vivo has not been determined.
Microsatellite instability is considered to result from defects in cells' DNA mismatch repair system.
Therefore, administration of chemotherapeutic drugs to patients with MSI(+) tumors may be ineffective.
However, MSI(+) tumors generally do not carry mutations in p53 or Rb, and thus gene therapy with these genes is unlikely to be effective.
To date, effective gene therapy methods for treating MSI(+) tumors have not been developed.

Method used

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  • Methods of detecting and treating microsatellite-instability positive tumors using RIZ
  • Methods of detecting and treating microsatellite-instability positive tumors using RIZ
  • Methods of detecting and treating microsatellite-instability positive tumors using RIZ

Examples

Experimental program
Comparison scheme
Effect test

example i

RIZ Mutations in MSI(+) Tumors, and Effect of Ectopic Expression of RIZ in MSI(+) Tumors

[0056] This example shows that RIZ poly(A)-tract frameshift mutations are present in a high percentage of MSI(+) tumor cells of a variety of different cell types. This example also shows that expression of a nucleic acid molecule encoding functional RIZ in an MSI(+) tumor cell containing a RIZ-poly(A)-tract frameshift mutation induces cell cycle arrest and apoptosis of the tumor cells.

Materials and Methods

[0057] Tissue Samples and Cell Lines. 22 MSI(−) tumors were studied. 8 of these were selected because they previously had been found to display a CIN (chromosomal instability) phenotype, including LOH at two closely linked markers, D1S228 [32.4 centimorgans (cM)] and D1S507 (36.2 cM) (Canzian et al., Cancer Res. 56:3331-3337 (1996)). In 14 tumors, the LOH status at 1p was unknown. Additionally, 3 MSI(−) lines were obtained from the American Type Culture Collection (ATCC). The MSI(−) lines we...

example ii

RIZ Poly(A)-Tract Frameshift Mutations in MSI(+) Gastric Cancers

[0076] This example shows that RIZ poly(A)-tract frameshift mutations occur with high frequency in MSI(+) gastric cancers.

[0077] To examine the role of RIZ in MSI(+) tumors, a total of 179 primary gastrointestinal and endometrial tumors from patients undergoing surgery were analyzed. Among them, 109 tumors were characterized as MSI-High, including 40 gastric carcinomas (K), 18 endometrial cancers (E or AN), and 51 colorectal cancers (AC, IC or AS). MSI-High status in primary tumors was defined according to the criteria proposed by Boland et al., supra (1998). The source of tumor samples is described in Kong et al., Nat. Genet. 17:143-144 (1997); Yamamoto et al., Cancer Res. 57:4420-4426 (.1997); and Kim et al., Lab. Investig. 79:1113-1120 (1999). A panel of MSI(+) cell lines derived from colon (HCTl16, SW-48, LOVO, LS44lN, LSl80, LSl74T, DLDl, HCTl5, HCT8), prostate (DUl45), breast (Cal-51), and uterus (AN3CA, SK-UT-1...

example iii

RIZ1 Expression Inhibits Growth of MSI(+) Tumors

[0086] This examples shows that RIZ1 expression inhibits growth of MSI(+) tumors and induces apoptosis of tumor cells in vivo.

[0087] To determine the efficacy of RIZl in gene therapy of MSI(+) tumors, the effect of expression of recombinant RIZl in inhibiting growth of established solid tumors was determined. As a control, the effect of recombinant p53 expression was also assessed.

[0088] The MSI(+) HCT116 colorectal cancer cell line (obtained from American Type Culture Collection), which carries homozygously mutated RIZl and wild type p53, was cultured in Dulbecco's modified Eagle's medium with 10% fetal calf serum.

[0089] Athymic female nu / nu (nude) mice were obtained from Jackson Laboratories-(Bar Harbor, Me.). HCT116 tumor cells (2×106 cells in 100 μl PBS / mouse) were injected subcutaneously into nude mice. Tumors were allowed to grow in vivo for 6 days, at which time they reached an average size of 0.5 cm in diameter. Prior to th...

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Abstract

The invention provides a method of inhibiting growth of a microsatellite instability (MSI)-positive tumor. The method is practiced by introducing into an MSI-positive tumor a nucleic acid molecule encoding a RIZ1 polypeptide and expressing the RIZ1 polypeptide in the tumor in an effective amount to inhibit growth of the tumor. Also provided is a method of determining the MSI status of a tumor. The method is practiced by determining in the tumor the number of adenosine (A) nucleotides in a poly(A) tract of a RIZ nucleic acid molecule in the tumor. An abnormal number of adenosine nucleotides in a RIZ poly(A) tract indicates that the tumor is MSI-positive.

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 60 / 256,582, filed Dec. 19, 2000, which is incorporated herein by reference.[0002] This invention was made in part with U.S. Government support under Grant No. RO1-CA76146 awarded by the National Institutes of Health. The U.S. Government has certain rights in this invention.BACKGROUND OF THE INVENTION [0003] 1. Field of the Invention [0004] The invention relates to the field of cancer and, more specifically, to methods for detecting and treating microsatellite-instability positive (MSI(+)) tumors using the RIZ tumor suppressor gene. [0005] 2. Background Information [0006] The retinoblastoma protein (Rb)-interacting zinc finger gene (RIZ) is a candidate tumor suppressor gene belonging to the PR (PRDI-BF1-RIZl homology) or SET (Suvar3-9, Enhancer-of-zeste, Trithorax) domain family of chromosomal regulators involved in chromatin-mediated gene activation and silencing. The PR / SET domain family plays an importa...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K48/00C12Q1/68
CPCC12Q1/6886C12Q2600/112C12Q2600/106
Inventor HUANG, SHICHADWICK, ROBERT
Owner THE BURNHAM INST
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